Cerebral neurons can probably tolerate at least 20 min of normothermic anoxia. After cardiac arrest (CA) of more than 5 min and cardiopulmonary resuscitation (CPR), however, the "post- resuscitation syndrome" of multiple organ systems normally precludes cerebral recovery. Our overall goals are: to help determine the biologic limits to and potentials for resuscitation from CA; and to identify measurements for reliable prediction of outcome. We hypothesize that post-CA, inadequate cerebral reperfusion and prolonged global hypoperfusion are key factors in permanent brain damage; that blood brain barrier leakage and cerebral edema may be factors in reduced blood flow; and that control of post-CA perfusion failure and edema can improve outcome. The specific aims of this project are to use an established dog model with CA of 10-15 min and long-term intensive care, to determine changes in cerebral and extracerebral variables and outcome, after: 1) uncontrollable reperfusion with CPR advanced life support (ALS) vs. controlled reperfusion and assisted circulation with cardiopulmonary bypass (CPB); 2) various reperfusion pressure patterns controlled by CPB; and 3) cerebral edema reducing hyperosmolar therapy. In an invasive, short-term 24-h model, global cerebral blood flow and metabolism will be monitored. In a noninvasive, long-term 6-d model, cerebral recovery will be determined by brain enzyme leakage into the CSF, overall performance categorization, neurologic deficit scoring, and histopathologic damage scoring. Cerebral edema and blood brain leakage will be monitored by NMR imaging. EEG spectrum, evoked potentials, and extracerebral variables will be monitored. In years 1 and 2 we propose to compare CPR-ALS with CPB (veno-arterial pumping via oxygenator, without thoracotomy, with heparinization and hemodilution), and study three different reperfusion pressure patterns controlled by CPB (normotenison, moderate hypertension, severe hypertension). In years 3 and 4 we propose to test a cerebral edema reducing therapy (e.g., mannitol i.v.) designed according to the results of years 1 and 2. Other related projects (not funded by this grant) will focus on post-CA multifocal hypoperfusion (1CBF by Xe enhanced CT), reoxygenation injury necrotizing cascades, intoxication from extracerebral organs, and blood-tissue interaction. Results will influence the protocols of future clinical trials of cardiac arrest and cardiopulmonary-cerebral resuscitation (our ongoing trial NS15295), and perhaps also the management of stroke, brain trauma and transplantation medicine.